Adrenal Gland

Outer cortex: Steroid hormones o Outer zona glomerulosa: minerelocorticoid hormone

Aldosterone: the principal minerelocorticoid Controlled by renin-angiotensin system

renin released from juxtaglomerular cells of the Kidney

Reduced renal perfusion pressure

decreased circulating blood volume

sympathetic stimulation Renin-Angiotensin 1- Angiotensin 11-

stimulate zona glomerulosa Aldosterone increases tranepithelial transport

of sodium by Kidney Promotes secretion of potassium

o Inner zona faciculata and reticularis: Glucocorticoids, androgens, estrogens

Major glucocorticoid: Cortisol Under control of ACTH(pituitary) which in turn

is regulated by CRF (hypothalamus) Negative feedback control Pulsatile secretion with diurnal variation

Inner medulla: Catecholamines o Sympathetic system

Adrenal cortical hypofunction

Primary o Combined Minerelocorticoid and Glucocorticoid

deficiency o Isolated Aldosterone deficiency

Secondary

o Hypopituitarism No Minerelocorticoid deficiency (not regulated

by ACTH) Hyperpigmentation is absent co-existent thyroid and gonadal deficiency

o Exogenous glucocorticoids o Hyporeninemic hypoaldosteronism

Symptoms of Addisons disease o Anorexia and weight loss o Weakness o Apathy o Hypotension / Hypovolemia o Inability to withstand stress o Hyponatremia o Hyperkalemia o Acidosis o Pigmentation - Increased ACTH o Increased renin

Etiology o Autoimmune process o Tuberculosis o Histoplasmosis o Metastatic carcinoma o Amyloidosis o Bilateral adrenal hemorrhage o Inherited disorders - biosynthetic enzymes

Diagnosis o subnormal plasma levels of cortisol and aldosterone o reduced urinary excretion of 17-hydroxycorticoids

and aldosterone-18-glucuronide o ACTH increased o ACTH stimulation- subnormal response o Increased renin

Treatment o IV fluids and supportive care

o Glucocorticoid Life long hydrocortisone Double the dose during minor stress 10x usual dose for major stress IV

hydrocortisone o Minerelocorticoid

High sodium chloride intake is sufficient in most

Fludrocortisone in selected cases with special attention

o Medic alert bracelet

Adrenal cortical hyperfunction

Glucocorticoid: Cushing's syndrome o Hypothalamic-pituitary abnormality (Cushing's

disease) Adenoma - small to be recognized in most

o Ectopic ACTH level of cortisol very high rapid onset mostly presents as electrolyte and acid base

disturbance not enough time for overt manifestations of

Cushing's syndrome Small cell cancer, Carcinoid, Medullary

carcinoma Thyroid o Primary adrenal tumor (Carcinoma, Adenoma)

(ACTH independant) o Exogenous Glucocorticoid therapy (ACTH

independant) Minerelocorticoid: Disturbance in electrolyte and blood

pressure homeostasis o Adrenal tumors: (Adenoma, Carcinoma) o Bilateral adrenal hyperplasia

o Adrenal enzyme defects o Exogenous minerelocorticoids (Licorice,

Carbenoxolone) Clinical manifestations

o Obesity (centripedal, buffalo hump, supraclavicular fat pads, moon facies)

o Carbohydrate intolerance o Muscle wasting o Osteoporosis o Easy bruisability o Abdominal striae o Hypertension o Mood swings, depression, psychosis o Hirsutism, acne, menstrual disorders

Diagnosis o Typical clinical features o Excess of hormone

Random serum cortisol level 24 hour urinary excretion of 17-hyrdoxy-

cortisol o Dexamethasone suppression test

Plasma cortisol >5 mcg/dl suggests Cushing's syndrome

o High dose Dexamethasone suppression test ACTH dependant: Pituitary (Cushing's

disease): 50% or greater suppression ACTH independant: Ectopic ACTH and

Adrenal tumors: No suppression o ACTH levels

Normal to slightly high in Cushing's disease Very high in ectopic ACTH secretion by

tumors Undetectable levels in Adrenal tumors

o CRH stimulation test

o MRI, High resolution CT scan, Contrast enhanced CT scan of Pituitary or Adrenal gland

Normal pituitary fossa does not rule out adenoma

Treatment o Surgery (Pituitary or adrenal or ectpic tumor) o Radiation o Inhibition of adrenalcortical secretion: Mitotane

Hypothalamus Pituitary inter relations

Hypothalamus o Hypothalamic peptides stimulate secretion of anterior

pituitary hormones o Dopamine inhibits prolactin secretion o Under neural regulation by variety of

neurotransmitters o Regulated by closed -loop feedback system o TRH, GnRF, CRF, GRF are releasing hormones

Anterior pituitary o Adenohypophysis o Derived from Rathke's pouch o Somatomammotropins

Growth hormone Prolactin / lactogenic Chorionic somatomamotropin

o Corticotrophin (ACTH) Stimulate secretion of glucocorticoid by

adrenal cortex

o Pituitary glycoprotein hormones Thyroid stimulating hormone (TSH) Follicle stimulating hormone (FSH)

Regulate ovulation and secretion of steroid by ovary

Leuteinizing hormone (LH) Regulate ovulation and secretion of

steroid by ovary Posterior pituitary

o Neurohypophysis o Anatomical extension of hypothalamus o Derived from diencephalon o Located in sella tursica o In the base of brain

Tests of anterior pituitary function o ACTH

ACTH / undetectable in normal basal state Deficiency: Stimulation by induced

hypoglycemia / of hypothalamus CRF not available for clinical use Hypothalamic problem

Positive CRF test Negative response to

hypoglycemia Pituitary problem

Negative CRF test Negative response to

hypoglycemia ACTH excess

Suppression with dexamethasone o TSH

Deficiency: TRH stimulation: TSH levels increase up to 15

Pituitary problem: Flat response

Hypothalamic problem: Normal response

Excess Flat response to TRH

o Gonadotropins Deficiency GnRH stimulation Clomiphere stimulation

Hypothalamic dysfunction Normal response to GnRH

stimulation Response to Clomiphere

stimulation Pituitary dysfunction

Excess o Prolactin o Growth hormone

Measurable Deficiency: stimulation by hypoglycemia, L-

dopa, GRF Excess: Glucose loading

Anterior pituitary hypofunction

Hypothalamic defect Pituitary gland defect Common Etiology

o Tumors o Granulomas o Vascular necrosis o Surgery o Radiation o Compression by a space occupying lesion

Clinical features o Growth hormone

Short stature Delayed puberty

o ACTH Symptoms of adrenal cortical deficiency

o TSH Symptoms of hypothyroidism

o Gonadotropin Amenorrhea Diminished libido Loss of pubic and axillary hair Atrophy of breast and Testis

Diagnosis o Differentiate from polyglandular deficiency states o Deficiency of major target organ products o Absence of compensatory increases of tropic

hormones of pituitary o Establish abnormality in the hypothalamic-pituitary-

axis o Use of stimulation studies o Use of hypothalamic releasing factors to distinguish

between Hypothalamic and pituitary dysfunction Treatment

o Replacement of specific hormones Caution in thyroid replacement. Concomitant

or preceding replacement of glucocorticoids o Treat etiology

Anterior pituitary hyperfunction

Usually benign slow growing tumors o Neurological symptoms (Headache) o Visual defects (bitemporal hemianopsia) o Pituitary insufficiency o Excessive secretion of any of the anterior pituitary

hormones

Prolactin / Galactorrhea Growth hormone / Acromegaly, Gigantism (in

young) ACTH / Cushing's syndrome

o Diagnosis Clinical picture Excess of the hormone Inability to suppress by physiological

maneuvers MRI and high resolution CT for evaluation of

tumor o Treatment options

Correct deficiencies Surgery Radiation Bromocriptine

Disorders of posterior pituitary

Oxytocin / Release of breast milk, promote uterine contraction in labor

Anitdiuretic hormone (ADH) / Regulates water metabolism o Response to serum osmolality, hypovolemia and

hypotension o Normal serum osmolality 285 o Acts on distal nephron to induce an increased water

permeability o Excess: Water intoxication. Syndrome of

inappropriate ADH secretion o Deficiency: Diabetes insipidus

Central vs Nephrogenic Central : due to hypothalamic rather than

pituitary problem

AVP is stored in pituitary but synthesized in the hypothalamus

Polyuria (>3 L/day) and polydypsia Dilute urine (sp gr <1010 or osmolality <300) Need to distinguish from psychogenic

polydypsia Water deprivation test followed by pitressin

o Treatment Chlorpropamide ADH replacement by nasal insufflations

Hypothyroidism

List common symptoms of hypothyroidism.

Answer

Weakness Fatigue Memory impairment Cold intolerance Constipation Loss of hair Hoarseness Deafness Menstrual irregularity

What are the physical findings of a patient with hypothyroidism?

Answer

Dry coarse skin Periorbital edema Coarse thin skin Thick tongue Slow speech Deep voice Delayed Achilles' tendon reflex time Bradycardia

What are the common etiologies for primary hypothyroidism?

Answer

Primary hypothyroidism

Hashimotto's thyroiditis Idiopathic Post therapy for hyperthyroidism External beam radiotherapy Lithium, Amiodarone Iodide deficiency

What historical information will help you in identifying the etiology for primary hypothyroidism?

Answer

Hashimotto's thyroiditis o Family history or the presence in the patient of other

autoimmune endocrine disease

o Schmidt's syndrome / Hashimotto's and pernicious anemia and diabetes mellitus

Idiopathic Post therapy for hyperthyroidism

o Radioactive iodine therapy / History of radioactive iodine therapy

o Subtotal thyroidectomy / History of thyroidectomy External beam radiotherapy / history of neck radiation for

lymphoma or head and neck cancer Lithium, amiodarone Iodide deficiency / underdeveloped countries

How does physical examination of the thyroid gland help in the differential diagnosis of hypothyroidism?

Answer

Hashimotto's thyroiditis o enlarged thyroid

Idiopathic o atrophic thyroid

Post therapy for hyperthyroidism o depends on etiology

External beam radiotherapy o radiation changes over thyroid (pigmentation,

induration) Lithium, Amiodarone

o goiter Iodide deficiency

o goiter

What are the common etiologies for secondary hypothyroidism?

Answer

Hypothalamic dysfunction Pituitary dysfunction

What are the common etiologies for secondary hypothyroidism due to hypothalamic dysfunction?

Answer

Therapeutic irradiation Hypothalamic tumors

o germinoma o meningioma o hamartoma

What are the symptoms and signs that would alert you to the possibility of hypothalamic lesion?

Answer

Diabetes insipidus Narcolepsy Excessive appetite Marked anorexia Hyperthermia Marked hypothermia

What are the common etiologies for secondary hypothyroidism due to pituitary dysfunction?

Answer

Pituitary dysfunction /secondary adrenal insufficiency, hypogonadism, growth hormone deficiency

o Pituitary tumor o Post partum pituitary necrosis o Sarcoidosis o Metastatic carcinoma involving pituitary,

hypothalamus or stalk o Rathke's cleft cyst, craniopharyngioma, carotid artery

aneurysm compressing pituitary

What are the signs and symptoms that would suggest pituitary tumor?

Answer

Space-occupying mass of pituitary

Headache Bitemporal hemianopsia 3rd, 4th, or 6th nerve defects Seizures Rhinorrhea Meningitis

What would make you suspect postpartum pituitary necrosis as the etiology for pituitary dysfunction?

Answer

History of shock or massive hemorrhage at time of delivery

Inability to breast feed Amenorrhea afterwards

Which tests would help confirm the diagnosis of hypothyroidism?

Answer

Total T4: Low Free T4: Low TSH Free T3: of no value

Which lab test helps you to distinguish primary from secondary hypothyroidism?

Answer

TSH o increased / primary o decreased / secondary

Baseline and dynamic anterior pituitary hormone testing for deficiencies and overproduction

How do you distinguish hypothalamic from pituitary dysfunction as the etiology for secondary hypothyroidism?

Answer

TRH stimulation:

Primary: Exaggerated TSH response. TSH levels increase up to 15

Pituitary: Flat TSH response Hypothalamus: Normal TSH response

Which tests helpful in the diagnosis of identifying a pituitary mass?

Answer

MRI with gadolinium enhancement to document the presence of a mass

Testing for other tumor markers (alpha subunits)

What are the common non-specific lab abnormalities of hypothyroidism?

Answer

CPK Anemia Bradycardia, low voltage and non specific ST T wave

changes Hypoxia with hypercapnea

What are the treatment options for primary hypothyroidism?

Answer

Thyroid hormone replacement therapy with non-generic l-thyroxin or a generic form that has undergone rigorous quality controlled supervision of the manufacturing process.

With risk factors for coronary arterial disease, it would be wise to start with a low dose of thyroid hormone and increase the dose slowly.

What are the treatment options for secondary hypothyroidism?

Answer

Evaluate if secondary hypoadrenalism is present If preset, treat simultaneously with the treatment of the

hypothyroidism Also evaluate whether hypogonadism and/or growth

hormone deficiency is present and treat accordingly Then treat the cause of the secondary hypothyroidism

What are the components of total serum thyroxin?

Answer

Free thyroxine 0.03% Thyroxine binding albumin 10% Thyroxine binding prealbumin 20% Thyroxine binding globulin 70%

Alterations in these binding proteins can alter serum thyroxine values and mistaken diagnosis of hypo or hyperthyroidism can be made.

Describe euthyroid hypothyroxinemia / sick syndrome.

Answer

Clinical picture Normal sized thyroid gland Low serum TBG Hypoalbuminemia / nephrotic syndrome, cirrhosis Low serum total T4 Normal free T4 Normal TSH Normal TSH response to TRH

What is sub clinical hypothyroidism?

Answer

Euthyroid Normal serum T4 and T3 Elevated TSH

Hyperthyroidism

What are the symptoms of hyperthyroidism?

Answer

Symptoms: Potentiation of sympathetic system by excess thyroxine

Nervousness Heat intolerance Palpitations

Tremor Weight loss in spite of voracious appetite Weakness particularly proximal muscle group Hyper defecation

What are the physical findings of hyperthyroidism?

Answer

Thyroid enlargement o pyramidal lobe o bruit

Potentiation of sympathetic system by excess thyroxine o lid lag o warm moist skin o fine tremor o brisk reflexes o tachycardia

Onycholysis / Plumber's nails Mucopolysaccharide infiltration

o proptosis o ophthalmopathy: diplopia o pretibial myxedema o clubbing/ thyroid acropachy

What are the common etiologies for hyperthyroidism?

Answer

� Grave's disease

� Toxic multinodular goiter

� Toxic adenoma

� Factitious thyrotoxicosis

� Toxic struma ovari

� Thyroiditis

How does physical examination of the thyroid help in the differential diagnosis of hyperthyroidism?

Answer

� Graves disease

o diffuse enlargement

o bruit

� Toxic multinodular goiter

o multiple nodules

� Toxic adenoma

o single nodule

� Factitious thyrotoxicosis

o small thyroid

� Toxic struma ovari

o small thyroid

� Thyroiditis

o diffuse enlargement

What tests are useful to confirm hyperthyroidism?

Answer

Total T4: high Free T4: High Free T3: High TSH: Decreased

What are the tests useful to distinguish Grave's disease from other causes?

Answer

RAIU/ Scintiscan o increased uptake / symmetrical goiter / Graves o heterogynous uptake / asymmetric / thyroiditis,

multinodular goiter o hot nodule / toxic adenoma o decreased / factitious and struma ovari and

thyroiditis TRAb TSI

Thyroid auto antibodies are insensitive TRH stimulation: flat TSH response in Grave's disease

Describe the lab findings in a patient with euthyroid hyperthyroxinemia, related to alteration in TBG.

Answer

High serum TBG Estrogens hepatitis, 5-fluorouracil High serum total T4 Normal free T4 Normal TSH

Describe the clinical and lab findings in a patient with euthyroid hyperthyroxinemia, unrelated to TBG levels.

Answer

Clinical picture Acute non-thyroidal illness, psychiatric illness, drugs Normal sized thyroid gland High serum total T4 High free T4 Unrelated to TBG

What are the treatment options for hyperthyroidism?

Answer

Antithyroid drug therapy Radioactive iodine therapy

Surgery Symptomatic therapy with beta blockers

What are the treatment options based on the etiology?

Answer

Graves disease o Induce euthyroid state with antithyroid drug therapy

first o Radioactive iodine therapy

majority preferred form of treatment o Surgery

for children large goiter

Toxic multinodular goiter o Induce euthyroid state with antithyroid drug therapy

first o Radioactive iodine therapy

majority o Surgery �

large goiter pressure complications from goiter

Toxic adenoma o Radioactive iodine therapy or o Surgery

Thyroiditis / symptomatic therapy only Factitious thyrotoxicosis / treat the personality problem

How would you treat a pregnant patient with hyperthyroidism?

Answer

Treat with antithyroid drugs only Surgery is rarely indicated Radioactive iodine therapy should never be used Close monitoring of newborn for thyroid function